Pulmonary arterial remodeling induced by a Th2 immune responseDaley, Eleen; Emson, Claire; Guignabert, Christophe; de Waal Malefyt, Rene; Louten, Jennifer; Kurup, Viswanath P.; Hogaboam, Cory; Taraseviciene-Stewart, Laimute; Voelkel, Norbert F.; Rabinovitch, Marlene; Grunig, Ekkehard; Grunig, Gabriele
doi: 10.1084/jem.20071008pmid: 18227220
Pulmonary arterial remodeling characterized by increased vascular smooth muscle density is a common lesion seen in pulmonary arterial hypertension (PAH), a deadly condition. Clinical correlation studies have suggested an immune pathogenesis of pulmonary arterial remodeling, but experimental proof has been lacking. We show that immunization and prolonged intermittent challenge via the airways with either of two different soluble antigens induced severe muscularization in small- to medium-sized pulmonary arteries. Depletion of CD4 + T cells, antigen-specific T helper type 2 (Th2) response, or the pathogenic Th2 cytokine interleukin 13 significantly ameliorated pulmonary arterial muscularization. The severity of pulmonary arterial muscularization was associated with increased numbers of epithelial cells and macrophages that expressed a smooth muscle cell mitogen, resistin-like molecule α, but surprisingly, there was no correlation with pulmonary hypertension. Our data are the first to provide experimental proof that the adaptive immune response to a soluble antigen is sufficient to cause severe pulmonary arterial muscularization, and support the clinical observations in pediatric patients and in companion animals that muscularization represents one of several injurious events to the pulmonary artery that may collectively contribute to PAH. Footnotes Abbreviations used: Asp Ag, Aspergillus fumigatus antigen; BALF, bronchoalveolar lavage fluid; H&E, hematoxylin and eosin; i.n., intranasal; PAH, pulmonary arterial hypertension; PCNA, proliferating cell nuclear antigen; RELM, resistin-like molecule; RVSP, right ventricular systolic pressure. E. Daley and C. Emson contributed equally to this work. Norbert F. Voelkel's present address is Victoria Johnson Center for Obstructive Lung Diseases, Virginia Commonwealth University, Richmond, VA 23284. Submitted: 21 May 2007 Accepted: 2 January 2008
Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseasesArmaka, Maria; Apostolaki, Maria; Jacques, Peggy; Kontoyiannis, Dimitris L.; Elewaut, Dirk; Kollias, George
doi: 10.1084/jem.20070906pmid: 18250193
Tumor necrosis factor (TNF) is key to the pathogenesis of various arthritic diseases and inflammatory bowel disease (IBD). Anti-TNF therapies have proved successful in the clinical treatment of these diseases, but a mechanistic understanding of TNF function is still lacking. We have investigated early cellular mechanisms of TNF function in these diseases using an established TNF transgenic model, which develops a spondyloarthritis-like disease characterized by peripheral joint arthritis, sacroiliitis, enthesitis, and Crohn's-like IBD. Bone marrow grafting experiments demonstrated that development of arthritis requires TNF receptor I (TNFRI) expression in the radiation-resistant compartment, which is also known to be a sufficient target of TNF in the development of Crohn's-like IBD in the same model. Early activation of synovial fibroblasts and intestinal myofibroblasts could also be demonstrated by perturbed expression of matrix metalloproteases and their inhibitors. Notably, selective Cre/loxP-mediated TNFRI expression in mesenchymal cells resulted in a fully arthritic–spondyloarthritic and intestinal phenotype, indicating that mesenchymal cells are primary and sufficient targets of TNF in these pathologies. Our results offer a novel mechanistic perspective for TNF function in gut and joint pathologies and indicate early common cellular pathways that may also explain the often observed synovial–gut axis in human disease. Footnotes Submitted: 7 May 2007 Accepted: 9 January 2008
Sustained desensitization to bacterial Toll-like receptor ligands after resolutionof respiratory influenza infectionDidierlaurent, Arnaud; Goulding, John; Patel, Seema; Snelgrove, Robert; Low, Lionel; Bebien, Magali; Lawrence, Toby; van Rijt, Leonie S.; Lambrecht, Bart N.; Sirard, Jean-Claude; Hussell, Tracy
doi: 10.1084/jem.20070891pmid: 18227219
The World Health Organization estimates that lower respiratory tract infections (excluding tuberculosis) account for ∼35% of all deaths caused by infectious diseases. In many cases, the cause of death may be caused by multiple pathogens, e.g., the life-threatening bacterial pneumonia observed in patients infected with influenza virus. The ability to evolve more efficient immunity on each successive encounter with antigen is the hallmark of the adaptive immune response. However, in the absence of cross-reactive T and B cell epitopes, one lung infection can modify immunity and pathology to the next for extended periods of time. We now report for the first time that this phenomenon is mediated by a sustained desensitization of lung sentinel cells to Toll-like receptor (TLR) ligands; this is an effect that lasts for several months after resolution of influenza or respiratory syncytial virus infection and is associated with reduced chemokine production and NF- κ B activation in alveolar macrophages. Although such desensitization may be beneficial in alleviating overall immunopathology, the reduced neutrophil recruitment correlates with heightened bacterial load during secondary respiratory infection. Our data therefore suggests that post-viral desensitization to TLR signals may be one possible contributor to the common secondary bacterial pneumonia associated with pandemic and seasonal influenza infection. Footnotes M. Bebien and T. Lawrence's present address is Institute of Cancer, Centre for Translational Oncology, Bart's and The London School of Medicine and Dentistry, London EC1M 6BQ, UK. Submitted: 3 May 2007 Accepted: 30 October 2007
Altered development of the brain after focal herpesvirus infection of the central nervous systemKoontz, Thad; Bralic, Marina; Tomac, Jelena; Pernjak-Pugel, Ester; Bantug, Glen; Jonjic, Stipan; Britt, William J.
doi: 10.1084/jem.20071489pmid: 18268036
Human cytomegalovirus infection of the developing central nervous system (CNS) is a major cause of neurological damage in newborn infants and children. To investigate the pathogenesis of this human infection, we developed a mouse model of infection in the developing CNS. Intraperitoneal inoculation of newborn animals with murine cytomegalovirus resulted in virus replication in the liver followed by virus spread to the brain. Virus infection of the CNS was associated with the induction of inflammatory responses, including the induction of a large number of interferon-stimulated genes and histological evidence of focal encephalitis with recruitment of mononuclear cells to foci containing virus-infected cells. The morphogenesis of the cerebellum was delayed in infected animals. The defects in cerebellar development in infected animals were generalized and, although correlated temporally with virus replication and CNS inflammation, spatially unrelated to foci of virus-infected cells. Specific defects included decreased granular neuron proliferation and migration, expression of differentiation markers, and activation of neurotrophin receptors. These findings suggested that in the developing CNS, focal virus infection and induction of inflammatory responses in resident and infiltrating mononuclear cells resulted in delayed cerebellar morphogenesis. Footnotes Abbreviations used: BDNF, brain-derived neurotrophic factor; BDV, Borna disease virus; CNS, central nervous system; EGL, external granular neuron layer; GNP, granule neuron precursor; HCMV, human cytomegalovirus; IE, immediate early; IGL, internal granular layer; IHC, immunohistochemical; MCMV, murine cytomegalovirus; ML, molecular layer; MuLV, murine leukemia virus; NT3, neurotrophin 3; PFA, paraformaldehyde; PN, postnatal. Submitted: 19 July 2007 Accepted: 8 January 2008
Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20Turer, Emre E.; Tavares, Rita M.; Mortier, Erwan; Hitotsumatsu, Osamu; Advincula, Rommel; Lee, Bettina; Shifrin, Nataliya; Malynn, Barbara A.; Ma, Averil
doi: 10.1084/jem.20071108pmid: 18268035
Toll-like receptors (TLRs) on host cells are chronically engaged by microbial ligands during homeostatic conditions. These signals do not cause inflammatory immune responses in unperturbed mice, even though they drive innate and adaptive immune responses when combating microbial infections. A20 is a ubiquitin-modifying enzyme that restricts exogenous TLR-induced signals. We show that MyD88-dependent TLR signals drive the spontaneous T cell and myeloid cell activation, cachexia, and premature lethality seen in A20-deficient mice. We have used broad spectrum antibiotics to demonstrate that these constitutive TLR signals are driven by commensal intestinal flora. A20 restricts TLR signals by restricting ubiquitylation of the E3 ligase tumor necrosis factor receptor–associated factor 6. These results reveal both the severe proinflammatory pathophysiology that can arise from homeostatic TLR signals as well as the critical role of A20 in restricting these signals in vivo. In addition, A20 restricts MyD88-independent TLR signals by inhibiting Toll/interleukin 1 receptor domain–containing adaptor inducing interferon (IFN) β–dependent nuclear factor κB signals but not IFN response factor 3 signaling. These findings provide novel insights into how physiological TLR signals are regulated. Footnotes Abbreviations used: BMDM, bone marrow–derived macrophage; HSC, hematopoietic stem cell; IRAK-M, IL-1R–associated kinase M; IRF, IFN response factor; MCP, monocyte chemoattractant protein; mRNA, messenger RNA; PAMP, pathogen-associated molecular pattern; poly (I:C), poly-inosine:cytosine; RIP, receptor-interacting protein; R.U., relative units; SIGIRR, single Ig and TIR domain; SOCS, suppressor of cytokine signaling; TIR, Toll/IL-1 receptor; TLR, Toll-like receptor; TRAF, TNF receptor–associated factor; TRIF, TIR domain–containing adaptor inducing IFN-β. E.E. Turer and R.M. Tavares contributed equally to this work. Submitted: 1 June 2007 Accepted: 11 January 2008
Vaccine protection against Staphylococcus aureus pneumoniaWardenburg, Juliane Bubeck; Schneewind, Olaf
doi: 10.1084/jem.20072208pmid: 18268041
Staphylococcus aureus pneumonia causes significant mortality in hospitalized or healthy individuals, and recent increases in morbidity are attributed to the rapid spread of methicillin-resistant S. aureus (MRSA) strains, which are often not susceptible to antibiotic therapy. α-Hemolysin (Hla), a secreted pore-forming toxin, is an essential virulence factor of MRSA in a mouse model of S. aureus pneumonia. We show that the level of Hla expression by independent S. aureus strains directly correlates with their virulence. Active immunization with a mutant form of Hla (Hla H35L ), which cannot form pores, generates antigen-specific immunoglobulin G responses and affords protection against staphylococcal pneumonia. Moreover, transfer of Hla-specific antibodies protects naive animals against S. aureus challenge and prevents the injury of human lung epithelial cells during infection. Thus, Hla vaccination or immunotherapy may prevent S. aureus pneumonia in humans. Footnotes Submitted: 15 October 2007 Accepted: 17 January 2008
IL-33 reduces the development of atherosclerosisMiller, Ashley M.; Xu, Damo; Asquith, Darren L.; Denby, Laura; Li, Yubin; Sattar, Naveed; Baker, Andrew H.; McInnes, Iain B.; Liew, Foo Y.
doi: 10.1084/jem.20071868pmid: 18268038
Atherosclerosis is a chronic inflammatory disease of the vasculature commonly leading to myocardial infarction and stroke. We show that IL-33, which is a novel IL-1–like cytokine that signals via ST2, can reduce atherosclerosis development in ApoE −/− mice on a high-fat diet. IL-33 and ST2 are present in the normal and atherosclerotic vasculature of mice and humans. Although control PBS-treated mice developed severe and inflamed atherosclerotic plaques in the aortic sinus, lesion development was profoundly reduced in IL-33–treated animals. IL-33 also markedly increased levels of IL-4, -5, and -13, but decreased levels of IFNγ in serum and lymph node cells. IL-33 treatment also elevated levels of total serum IgA, IgE, and IgG 1 , but decreased IgG 2a , which is consistent with a Th1-to-Th2 switch. IL-33–treated mice also produced significantly elevated antioxidized low-density lipoprotein (ox-LDL) antibodies. Conversely, mice treated with soluble ST2, a decoy receptor that neutralizes IL-33, developed significantly larger atherosclerotic plaques in the aortic sinus of the ApoE −/− mice compared with control IgG-treated mice. Furthermore, coadministration of an anti–IL-5 mAb with IL-33 prevented the reduction in plaque size and reduced the amount of ox-LDL antibodies induced by IL-33. In conclusion, IL-33 may play a protective role in the development of atherosclerosis via the induction of IL-5 and ox-LDL antibodies. Footnotes Submitted: 29 August 2007 Accepted: 14 January 2008